Abstract: We are applying to the RR&D Cooperative Program in Translational Research to seek funding to complete the preclinical steps required to obtain IND and IRB approval of a glutamic acid decarboxylase (GAD)-expressing herpes simplex virus (HSV)-based vector for a phase 1/2 clinical trial in patients with painful diabetic neuropathy (PDN). The development of novel effective treatments for chronic pain has been disappointingly slow, in part because the conservative use of a limited repertoire of neurotransmitters, receptors and ion channels in the nervous limits our ability to employ systemically administered small molecules to selectively interrupt nociceptive neurotransmission. To overcome this limitation we have constructed a series of non- replicating HSV-based vectors that efficiently target gene delivery to dorsal root ganglia from skin inoculation to effect the release of antinociceptive neurotransmitters in dorsal horn of spinal cord. We have taken the first of these vectors - a nonreplicating HSV vector expressing preproenkephalin - into phase 1 clinical trial in patients with intractable pain from cancer. There is a substantial unmet need for effective treatments of neuropathic pain; preclinical animal studies demonstrate that the GAD-expressing HSV vector is effective in a rodent model of PDN; and the VA has an ownership stake in the patent (under review) for this vector. Successful completion of the work proposed will allow the vector to be tested in patients. PUBLIC HEALTH RELEVANCE: Project Narrative We are applying to the RR&D Cooperative Program in Translational Research to seek funding to complete the preclinical steps required to obtain IND and IRB approval of a glutamic acid decarboxylase (GAD)-expressing herpes simplex virus (HSV)-based vector for a phase 1/2 clinical trial in patients with painful diabetic neuropathy (PDN). There is a substantial unmet need for effective treatments of neuropathic pain; preclinical animal studies demonstrate that the GAD-expressing HSV vector is effective in a rodent model of PDN; and the VA has an ownership stake in the patent (under review) for this vector. Successful completion of the work proposed will allow the vector to be tested in patients.